This is a proposal for a Small Grant (R03) from a new Investigator for a new research project to investigate the impact of female hormones on the stress responsiveness of the nucleus locus coeruleus (LC)-noradrenergic system. The existence of gender differences in vulnerability to psychiatric disorders has been well documented. Many of the disorders that are more prevalent in females have also been linked to stress (i.e., depression, anorexia nervosa) suggesting that gender differences in substrates of the stress response may underlie this differential vulnerability. Consistent with this, stress-induced activity of the hypothalamic-pituitary-adrenal axis is enhanced in females and this has been attributed to effects of estrogen on corticosteroid receptor function and increased expression of corticotropin-releasing factor (CRF), the neurohormone that initiates the endocrine limb of the stress response. Activation of the LC-noradrenergic system is another important component of the stress response and evidence suggests that this may be mediated by neurotransmission of CRF and endogenous opioids. The proposed AIMS test the hypothesis that gonadal hormones regulate CRF and/or endogenous opioid neurotransmission in the LC, thereby altering LC response to acute physiological stress in a naive milieu; also determining the influence of gonadal hormones on long-term adaptive alterations native to a prior stress milieu by evaluating the response of LC neurons to an acute stress after exposure to a prior stress. As activation of the LC-noradrenergic system by stress is thought to play a role in arousal and attention, gonadal hormone associated dysfunction of these cognitive components, in particular, and dysfunction of LC responses to stress, in general, could underlie gender differences in vulnerability to stress-related psychiatric disorders.